This article briefly describes the proteins and various cellular processes that go wrong in Parkinson's disease such as neuroinflammation, oxidative stress, mitochondrial dysfunction and alpha-synuclein misfolding.
What goes wrong
Parkinson’s disease is mainly caused by the loss of dopaminergic neurons from the pars compacta – a part of the substantia nigra in the midbrain – that causes rigidity, resting tremor and slowness of movement (bradykinesia)1, along with the presence of intracellular protein aggregates called Lewy bodies.
The neurotransmitter dopamine is responsible for coordinating movement and is produced by dopaminergic neurons. The loss of these neurons reduces the dopamine level, causing the distinctive motor symptoms of Parkinson’s disease.
Generally, motor symptoms occur when there is an extensive loss of dopaminergic neurons. When misfolded α-synuclein or alpha-synuclein aggregates into oligomers and produces β-sheet-rich fibrils, Lewy bodies are formed. Misfolded α-synuclein moves in a prion-like fashion between neurons2, where it behaves as a template to cause misfolding of normal α-synuclein. It is believed that proteins including α-synuclein accumulate long before the loss of neurons3.
In spite of the occurrence of Lewy bodies in neuronal loss regions, it has always been hard to determine whether their presence is associated with cell death. Whether these Lewy bodies are neurotoxic or protective is still a debatable topic.
Yet, new evidence from multiphoton imaging in mice has demonstrated selective death of these Lewy body-containing neurons4. This suggests that the presence of these Lewy bodies is tightly associated with cellular toxicity and hence could be a pathologically related event in the progression of Parkinson’s disease.
Usually, Parkinson's disease occurs intermittently with less than 10% of patients having a familial component5. The following section outlines the causes of Parkinson's disease along with abnormal protein aggregation and degradation and oxidative stress.
Parkinson’s disease is caused by mutations in six genes (SNCA, LRRK2, PRKN, DJ1, PINK1 and ATP 13A2)6,7. Risk factors include loss-of-function mutations in the GBA gene and polymorphisms in three genes such as SNCA, LRRK2 and MAPT 6.
Protein aggregation and misfolding
The most critical factor that contributes to the development of Parkinson’s disease is aggregation and misfolding of α-synuclein8. Misfolded α-synuclein impairs protein caretaking systems such as the autophagy-lysosome pathway (ALP) and the ubiquitin-proteasome system (UPS).
This results in a feedback loop in which α-synuclein builds up, which further suppresses the ALP and UPS function and ultimately leads to neuronal death10,11. It was recently shown that the normal ALP function and the long-term survival and integrity of dopaminergic neurons are tied to the transcription factor Lmx1b12,13.
In Parkinson’s disease, dopamine loss causes oxidative stress. Monoamine oxidase-B metabolizes dopamine resulting in the formation of hydrogen peroxide. When excess amounts of hydrogen peroxide are present in the cell, they are generally cleared by glutathione (GSH). If this does not occur, it will result in the production of reactive oxygen species (ROS) that can initiate a cytotoxic cascade of lipid peroxidation and eventually lead to cell death.
The combination of reduced GSH levels in Parkinson’s disease brains14 and a high dopamine turnover (a kind of compensatory mechanism for reduced dopaminergic neurons) causes high peroxidation levels and cellular damage.
Another product of spontaneous and enzymatic dopamine oxidation is DA quinine, which can cause mitochondrial dysfunction or alter several proteins, such as UCH-L1, DJ-1, α-synuclein and parkin, whose dysfunctions are associated with the pathophysiology of Parkinson’s disease15,16.
Parkinson’s disease pathogenesis occurs when there is excessive mitochondrial damage. Processes like genetic-induced alterations, lipid membrane peroxidation by ROS and reduced activity of complex I in the electron transport chain can cause mitochondrial damage, which can release cytochrome c and trigger apoptosis15,16.
For instance, Parkin and PINK1 localize to mitochondria and are linked to normal function17. When PINK1 builds up on the outer membrane of dysfunctional mitochondria, it recruits parkin to the damaged mitochondria and triggers mitophagy18. When there is a buildup of dysfunctional mitochondria, it results in a medical condition called early-onset Parkinson’s disease18.
Since dopaminergic neurons produce high levels of ROS, they are extremely sensitive to the chain of oxidative stress events. The gradual loss of these neurons can lead to chronic neuroinflammation via the activation of microglia by DJ-10, LRRK2, parkin and α-synuclein proteins 19,20.
Chronically or overactive activated microglia tends to release ROS21 and promote an unregulated inflammatory response, which creates a self-perpetuating cycle of neurodegeneration22.
LRRK is likely to be the main modulator of neuroinflammation23. It is highly induced in response to the overexpression of α-synuclein protein, whilst LRRK2 knockout rats are not susceptible to dopaminergic neurodegeneration and neuroinflammatory responses after the overexpression of α-synuclein24.
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